AMP-activated protein kinase and pancreatic/duodenal homeobox-1 involved in insulin secretion under high leucine exposure in rat insulinoma beta-cells.
AMP-activated protein kinase and pancreatic/duodenal homeobox-1 involved in insulin secretion under high leucine exposure in rat insulinoma beta-cells.
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DOI：
10.1111/j.1582-4934.2009.00656.x
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发表时间：
2009-04
影响因子：
5.3
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Zhang X;Sun N;Wang L;Guo H;Guan Q;Cui B;Tian L;Gao L;Zhao J
亮氨酸对胰腺β-细胞葡萄糖刺激的胰岛素分泌的影响存在较大争议，其作用机制尚不清楚。因此，我们旨在研究亮氨酸对GSIS的影响及其机制，重点是AMP激活的蛋白激酶(AMPK)和胰腺/十二指肠同源盒-1(PDX-1)的作用。大鼠胰岛素瘤β细胞(INS-1、RIN m5F、DN-PDX-1#28和PDX-1#6)在加或不加亮氨酸、腺苷酸激酶激动剂或化合物C的条件下培养48小时。与对照组相比，AICAR治疗降低了高糖和胰岛素水平下的GSIS，也损害了PDX-1及其下游靶标葡萄糖激酶(GCK)和葡萄糖转运蛋白2(GLUT2)的蛋白和mRNA表达。化合物C处理的效果正好相反。我们观察到，当PDX-1表达缺失时，AICAR和化合物C都不影响GCK和GLUT2的表达。慢性亮氨酸暴露以剂量依赖的方式抑制高糖和胰岛素含量下的GSIS，伴随着AMPK的增加和PDX-1、GCK和GLUT2的减少。AICAR可增强亮氨酸的抑制作用，化合物C可拮抗其抑制作用。抑制PDX-1可以增强亮氨酸对细胞的损伤作用，而过表达PDX-1可以保护细胞免受亮氨酸的损伤。提示慢性亮氨酸可能导致AMPK升高，PDX-L降低，进而抑制GCK和GLUT2，导致高糖、高胰岛素状态下GSIS降低。
The effect of leucine on glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is quite controversial, and mechanism involved in the effect has not been elucidated yet. Consequently, we aimed to investigate effect of leucine on GSIS and its mechanism focusing on contribution of AMP-activated protein kinase (AMPK) and pancreatic/duodenal homeobox-1 (PDX-1). Rat insulinoma β-cells (INS-1, RIN m5F, DN-PDX-1#28 and PDX-1#6) were cultured with or without leucine, AICAR (AMPK agonist) or compound C (AMPK antagonist) for 48 hrs. In contrast to control, AICAR treatment decreased GSIS at high glucose and insulin content, also impaired protein and mRNA expression of PDX-1 and its downstream targets, glucokinase (GCK) and glucose transporter 2 (GLUT2). Compound C treatment had the opposite effects. We observed that neither AICAR nor compound C could affect expression of GCK and GLUT2 when PDX-1 expression was absent. Chronic leucine exposure inhibited GSIS at high glucose and insulin content in a dose-dependent manner, concomitant with an increase in AMPK and a decrease in PDX-1, GCK and GLUT2. The inhibitory effects of leucine was potentiated by AICAR treatment and rescued by compound C treatment. Finally, the inhibition of PDX-1 could potentiate the impaired effects induced by leucine whereas overexpression of PDX-1 could protect the cell from impairment induced by leucine. The study indicated that chronic leucine might result in an increase in AMPK and then a decrease in PDX-l, in turn to depress GCK and GLUT2 resulting in decreased GSIS at high glucose and insulin content.
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影响因子：
3.8
作者：
Jiang Y;Ahn EY;Ryu SH;Kim DK;Park JS;Yoon HJ;You S;Lee BJ;Lee DS;Jung JH
通讯作者：
Jung JH
影响因子：
64.8
作者：
JONSSON, J;CARLSSON, L;EDLUND, H
通讯作者：
EDLUND, H
影响因子：
9.8
作者：
Alstrup, KK;Brock, B;Hermansen, K
通讯作者：
Hermansen, K
影响因子：
4.5
作者：
Bolea, S;Pertusa, JAG;Soria, B
通讯作者：
Soria, B
影响因子：
4.8
作者：
Iype, T;Francis, J;Mirmira, RG
通讯作者：
Mirmira, RG